Management of sleep apnoea syndrome.
Obstructive sleep apnoea is a chronic condition characterized by repetitive episodes of upper airway collapse during sleep, leading to sleep fragmentation. The management of sleep apnoea consists of general and specific measures. General measures should include weight loss in overweight patients; avoidance of alcohol during the evening hours; avoidance of any hypnotic drug. Specific measures may range from simple position training in patients with positional sleep apnoea (sleep apnoea appearing only when lying on the back) of slight severity; to oral appliances with the aim of creating a prognathism during sleep, to the introduction of a nasopharyngeal tube during sleep every night. When position training, oral appliances or a nasopharyngeal tube are used, their effect should be monitored by full night polysomnography. The best specific treatment for sleep apnoea is nasal continuous positive airway pressure. The main problem with nasal continuous positive airway pressure is the long-term compliance which should be assessed regularly over the years. In cases where nasal continuous positive airway pressure is not tolerated or compliance is bad, a surgical treatment can be proposed. Uvulopalatopharyngoplasty seems to give disappointing results. By contrast, maxillomandibular surgery is credited with the best results available as far as surgery is concerned, comparable to nasal continuous positive airway pressure.


A comparative study of affibody, panitumumab, and EGF for near-infrared fluorescence imaging of EGFR- and EGFRvIII-expressing tumors.
Aberrant overexpression and/or activation of epidermal growth factor receptor (EGFR) is associated with many types of cancers. EGFR variant III (EGFRvIII) is a common in-frame deletion mutant, which lacks a large part of the extracellular portion (exons 2-7), including components of the ligand-binding domain. Although EGFR has been extensively studied as a molecular imaging target, information about EGFRvIII-targeted molecular imaging is lacking. In this study, the EGFR-specific affibody, therapeutic antibody panitumumab, and ligand EGF were labeled with IRDye 800CW (Ex/Em: 774/789 nm), yielding Aff800, Pan800, and EGF800, respectively. The binding affinities of the labeled agents were compared in cell-based assays using a rat glioma cell line F98 parental (F98-p) lacking EGFR expression, and 2 F98-derived transgenic cell lines expressing EGFR or EGFRvIII (designated as F98-EGFR and F98-vIII, respectively). Results showed that all agents could bind to F98-EGFR, with Pan800 having the highest binding affinity, followed by Aff800 and EGF800. Pan800 and Aff800, but not EGF800, also bound to F98-vIII. In vivo animal imaging demonstrated that compared with F98-p tumors, F98-EGFR tumors generated higher signals with all three agents. However, in the case of F98-vIII, only Pan800 and Aff800 signals were higher. Analysis of tissue lysates showed that a large portion of Pan800 was degraded into small fragments in F98-EGFR and F98-vIII tumors, possibly due to proteolytic digestion after its specific binding and internalization. In conclusion, Pan800 and Aff800 could be used as imaging agents for both wild-type EGFR and EGFRvIII, whereas EGF800 only targets wild-type EGFR.


Survival determinants in extensive-stage non-small-cell lung cancer: the Southwest Oncology Group experience.
We analyzed the 2,531-patient Southwest Oncology Group extensive-stage non-small-cell lung cancer (ENSCLC) data base from 1974 to 1988 to (1) assess the interactions of host- or tumor-related prognostic factors and therapy using Cox modeling and recursive partitioning and amalgamation (RPA) to determine whether each independently predicts outcome, and (2) use RPA to define prognostic subsets with different survival potentials. Good performance status (PS), female sex, and age greater than or equal to 70 years were significant independent predictors in a Cox model applied to the entire population. In a second Cox model for patients with good PS enrolled on recent studies, hemoglobin level greater than or equal to 11.0 g/dL, normal lactate dehydrogenase (LDH), normal calcium, and a single metastatic site were significant favorable factors. The use of cisplatin was an additional independent predictor of improved outcome in both Cox models after adjustments for year of accrual and all prognostic variables. The favorable effect of cisplatin was observed in each of six RPA-derived subgroups from the entire population. A second RPA of 904 patients from recent trials (nearly all received cisplatin-based therapy) resulted in three distinct prognostic subsets based on PS, age, hemoglobin, and LDH; greater than or equal to 1-year survivals were 27%, 16%, and 6% (P less than .0001). The best survival occurred for patients with a good PS who had a hemoglobin level greater than or equal to 11 g/dL and who were older than 47 years. This analysis suggests that although several factors were independent variables in the Cox models, three important prognostic subgroups were easily defined through RPA. Together with other analyses, our results suggest the need to modify the stage IV category in NSCLC.


Passive, one-dimensional countercurrent models do not simulate hypertonic urine formation.
Simulations were performed to test the ability of the countercurrent hypothesis to predict measured concentrations of NaCl and urea in the interstitium of the renal medulla. The simulations included one-dimensional representations of loops of Henle, distal tubules, collecting ducts, and vasa recta, and recent estimates of descending limb, thick ascending limb, and collecting duct transport parameters. The nonlinear two-point boundary value problem was solved numerically via quasi-linearization. The simulations failed to predict measured concentrations or concentration gradients of NaCl in the inner medulla. Including countertransport of urea and NaCl in thin ascending limbs added minimally to the performance of the system. The single most effective change in the model was the inclusion of a coefficient to permit preferential solute exchange among vasa recta. This result suggests that the three-dimensional ordering of blood vessels and tubules is an essential construct in the concentrating mechanism.


Nonlinear optical properties of nanocrystalline diamond.
We report on investigation of nonlinear optical phenomena in nanocrystalline diamond prepared by microwave plasma enhanced chemical vapour deposition. We observed the upconverted photoluminescence, the second and the third harmonic generation and Z-scan signal. The value of the third order nonlinear susceptibility was estimated. Our results show that nonlinear optical properties of nanocrystalline diamond have many features of the bulk diamond affected to some extent by the presence of grain boundaries.


Studies on the biosynthesis of pancreatic glucagon in the pigeon (Columba livia).
The biosynthesis of glucagon was studied in microdissected pigeon pancreatic, islets. [3H]-Tryotophan and [3H]leucine were incorporated into big and little glucagon. No precursor-product relationship was evident between big and little glucagon after radioactive pulsechase and immunoreactive chase incubations. Radioactive and immunoreactive little glucagon and immunoreactive big glucagon were actively secreted and the synthesis of both glucagons was inhibited by high concentrations of glucose. [3H]Tryptophan and [3H]leucine were incorporated into an islet protein of about 20000mol.wt. Gel filtration of extracts of turkey pancreas revealed the presence of an immunoreactive peak of mol.wt. approx. 20000. This glucagon-immunoreactive component was also present in dog and ox pancreas and was stable to chaotropic agents and elution at various pH values. A similar-sized glucagon-immunoreactive species was present in the dog circulation. These results are discussed in the light of the presently accepted mechanisms of glucagon biosynthesis.


Role of Rho and Rho kinase in the activation of volume-regulated anion channels in bovine endothelial cells.
1. We have studied the modulation of volume-regulated anion channels (VRACs) by the small GTPase Rho and by one of its targets, Rho kinase, in calf pulmonary artery endothelial (CPAE) cells. 2. RT-PCR and immunoblot analysis showed that both RhoA and Rho kinase are expressed in CPAE cells. 3. ICl,swell, the chloride current through VRACs, was activated by challenging CPAE cells with a 25 % hypotonic extracellular solution (HTS) or by intracellular perfusion with a pipette solution containing 100 microM GTPgammaS. 4. Pretreatment of CPAE cells with the Clostridium C2IN-C3 fusion toxin, which inactivates Rho by ADP ribosylation, significantly impaired the activation of ICl,swell in response to the HTS. The current density at +100 mV was 49 +/- 13 pA pF-1 (n = 17) in pretreated cells compared with 172 +/- 17 pA pF-1 (n = 21) in control cells. 5. The volume-independent activation of ICl,swell by intracellular perfusion with GTPgammaS was also impaired in C2IN-C3-pretreated cells (31 +/- 7 pA pF-1, n = 11) compared with non-treated cells (132 +/- 21 pA pF-1, n = 15). 6. Activation of ICl,swell was pertussis toxin (PTX) insensitive. 7. Y-27632, a blocker of Rho kinase, inhibited ICl,swell and delayed its activation. 8. Inhibition of Rho and of Rho kinase by the above-described treatments did not affect the extent of cell swelling in response to HTS. 9. These experiments provide strong evidence that the Rho-Rho kinase pathway is involved in the VRAC activation cascade.


Quantitative RT-PCR: limits and accuracy.
In this paper we determine the limits and accuracy of quantitative reverse transcription (RT)-PCR using a modification of the original protocol. The quantification of mRNA with this procedure requires a preliminary estimation of the target molecule (TM) concentration, established from experiments with an internal control molecule (ICM). A definitive quantification is then attained from serial dilutions of the reverse transcription reaction. The success of this latter step is dependent on maintaining an equivalent number of TM and ICM in the reaction. The purpose of our study was to evaluate the influence of the deviation between the TM and the ICM on the result. We show here that we can control the accuracy of the assay by fixing the limit of the TM/ICM ratio. Indeed, when the TM/ICM ratio is between 0.66 and 1.5 (i.e., the difference between TM and ICM is 1.5-fold), the final result has an error of approximately 10%. Exceeding this limit produces errors approaching 60%, as in the case of TM/ICM = 2. When the above conditions are respected, a difference as small as 20% between two samples can be determined with an accuracy of 95%.


Detection and genetic diversity of porcine group A rotaviruses in historic (2004) and recent (2011 and 2012) swine fecal samples in Ohio: predominance of the G9P[13] genotype in nursing piglets.
Epidemiological surveillance of porcine group A rotavirus (RVA) strains was conducted in five swine herds in Ohio using historical (2004) and recent (2011 to 2012) fecal samples. Of the 371 samples examined, 9.4% (35/371) were positive for RVA. The RVA detection rates increased from 5.9% in 2004 and 8.5% in 2011 to 13.8% in 2012. A total of 23 positive samples were analyzed for RVA G and P genotypes. The dominant G-P combination was G9P[13] found in 60.9% of positive samples. The other combinations were G9P[7] (8.7%), G4P[13] (8.7%), G11P[13] (4.3%), and G11P[7] (4.3%). Sequence analysis of partial VP7 genes of selected strains revealed that the G4 strains were closely related to one another (95%) and, to a lesser extent, to human (82 to 84%) and porcine (84 to 86%) G4 strains. The G11 strains detected shared identical VP7 gene sequences (100%) and were closely related to human (85 to 86%) and other porcine (83%) G11 strains. The G9 strains identified were closely related to one another and to human and other porcine strains (96 to 97%, 89 to 91%, and 89 to 91% nucleotide identities, respectively). The VP4 gene analysis revealed that P[7] strains were closely related to each other and to P[7] strains isolated from porcine, bovine, and panda samples (91 to 99%, 92 to 99% and 92 to 99%, respectively). The P[13] strains showed a higher diversity among themselves and with other porcine P[13] strains, ranging from 83% to 99% and from 82 to 97%, respectively. Our results demonstrate broad genetic heterogeneity of the RVA strains and suggest the possibility of genetic reassortment between different RVA genotypes within these farms.


Evaluating the performance of ChatGPT in clinical pharmacy: A comparative study of ChatGPT and clinical pharmacists.
To evaluate the performance of chat generative pretrained transformer (ChatGPT) in key domains of clinical pharmacy practice, including prescription review, patient medication education, adverse drug reaction (ADR) recognition, ADR causality assessment and drug counselling. Questions and clinical pharmacist's answers were collected from real clinical cases and clinical pharmacist competency assessment. ChatGPT's responses were generated by inputting the same question into the 'New Chat' box of ChatGPT Mar 23 Version. Five licensed clinical pharmacists independently rated these answers on a scale of 0 (Completely incorrect) to 10 (Completely correct). The mean scores of ChatGPT and clinical pharmacists were compared using a paired 2-tailed Student's t-test. The text content of the answers was also descriptively summarized together. The quantitative results indicated that ChatGPT was excellent in drug counselling (ChatGPT: 8.77 vs. clinical pharmacist: 9.50, P = .0791) and weak in prescription review (5.23 vs. 9.90, P = .0089), patient medication education (6.20 vs. 9.07, P = .0032), ADR recognition (5.07 vs. 9.70, P = .0483) and ADR causality assessment (4.03 vs. 9.73, P = .023). The capabilities and limitations of ChatGPT in clinical pharmacy practice were summarized based on the completeness and accuracy of the answers. ChatGPT revealed robust retrieval, information integration and dialogue capabilities. It lacked medicine-specific datasets as well as the ability for handling advanced reasoning and complex instructions. While ChatGPT holds promise in clinical pharmacy practice as a supplementary tool, the ability of ChatGPT to handle complex problems needs further improvement and refinement.


Antioxidant properties of breast milk in a novel in vitro digestion/enterocyte model.
There is good evidence to suggest that human breast milk has antioxidant properties. Our primary goal was to investigate the antioxidant properties of human milk in a combined in vitro digestion/cell culture model that more closely replicates conditions in the gastrointestinal system of the preterm infant. An in vitro digestion model was developed that incorporates both gastric and intestinal phases, based on reported luminal pH, digestive enzyme levels, and transit times observed in preterm infants. To mimic the human intestinal mucosa, 2 cell lines--Caco-2BBE and HT29-MTX--were cocultured on Matrigel, an artificial basement membrane substrate. Intracellular oxidative stress was measured with 2 broadly selective oxidant-sensitive dyes, and oxidative DNA damage was assessed by means of single-cell gel electrophoresis. Enterocyte differentiation and mucin secretion were observed by 14 seeding of cultures. Direct exposure to digested milk resulted in a loss of transepithelial electrical resistance; however, exogenous mucin mitigated this loss. Data suggested that both milk and digested milk alleviated oxidative stress in the coculture, and both reduced hydrogen peroxide-induced oxidative DNA damage, as demonstrated by the comet assay. Our results support the hypothesis that breast milk reduces oxidative stress in a cell culture model representative of the intestinal mucosa, and also confirmed the suitability of this combined in vitro digestion/cell culture system for investigating the physiologic effects of enteral nutrients such as breast milk, under conditions similar to those existing in the gastrointestinal system of the preterm infant.


Immunohistochemical localization of NQO1 in epithelial dysplasia and neoplasia and in donor eyes.
To examine the expression of NAD(P)H:quinone oxidoreductase 1 (NQO1, DT-diaphorase), a potential bioactivating enzyme for mitomycin C in corneal and conjunctival epithelial dysplasia and neoplasia and in normal tissues from human donor eyes, by immunohistochemistry. Formalin-fixed, paraffin-embedded sections of human donor eyes and tissue sections with histologic diagnoses of corneal and conjunctival epithelial dysplasia and neoplasia from the Eye Pathology Laboratory, University of Colorado Health Sciences Center were analyzed. Detection of NQO1 in tissues was performed using standard immunohistochemical techniques with monoclonal antibodies against NQO1 and immunoperoxidase staining. All 20 tumors stained positive for NQO1. In seven eyes from four donors, positive staining for NQO1 was detected in all epithelial and endothelial layers, in fibroblasts, in all retinal layers except the photoreceptor outer segments, and in the fascicles and arachnoid of the optic nerve. Only minimal staining was detected in the photoreceptor outer segments and the optic nerve pia and dura. Immunostaining was markedly reduced in all tissues in both eyes from donor 5. Genetic analysis confirmed that this individual was homozygous for a polymorphism in NQO1 (NQO1*2). NQO1 was detected by immunohistochemistry in every examined section of corneal and conjunctival epithelial dysplasia and neoplasia, suggesting that NQO1 may play a role in the bioactivation of mitomycin C in these tumors. However, the presence of NQO1 in the corneal, conjunctival, and ciliary epithelium; the retinas; and the optic nerves of donor eyes may indicate the potential for mitomycin C toxicity, particularly at higher doses.


A Pilot and Feasibility Study of Oatmeal Consumption in Children to Assess Markers of Bowel Function.
Inadequate dietary fiber intake contributes to irregular bowel movements and may contribute to difficulty with defecation in children. Whole grain foods, such as oatmeal, may improve stool consistency and stool frequency in children; however, no studies have examined its effects. The purpose of this study was to investigate if 2 weeks of oatmeal consumption in children (ages 7-12 years) increases stool frequency, improves stool consistency, and gastrointestinal (GI) symptoms. In this single-arm intervention study, children who reported ≤5 bowel movements per week during screening, consumed two servings of instant oatmeal daily for 2 weeks. The primary outcome was stool frequency and secondary outcomes included stool consistency and GI symptoms. Participants recorded bowel movements daily, food intake, and GI symptoms during baseline and 2 intervention weeks. Photos of the children's stool were taken at three timepoints during the study to assess stool consistency. In total, 33 children (15 female and 18 male) completed the study. Linear mixed models were used to detect change between baseline and the intervention weeks and accounted for repeated measures within subjects. No statistical differences in stool frequency or consistency were observed between the intervention weeks vs. baseline; however, dietary fiber intake significantly increased during the 2 weeks of oatmeal consumption (P = .008). The addition of oatmeal to children's diets is an effective way to increase fiber consumption and may reduce some GI symptoms such as gas, straining, and feeling of incomplete evacuation. Trial identification number: NCT02868515.


The cellular and physiologic effects of beta blockers in heart failure.
Enhanced and sustained cardiac adrenergic drive occurs in heart failure (HF) and contributes, in part, to the progression of left ventricular (LV) dysfunction and remodeling that are characteristic of this disease state. Enhanced sympathetic drive in HF can lead to downregulation and desensitization of cardiac beta-adrenergic receptors with a consequent impairment of myocardial reserve and exercise tolerance. This sympathoadrenergic maladaptation can also lead to cellular abnormalities in the failing heart, manifested by defects in calcium handling of the sarcoplasmic reticulum, by defects in myocardial energetics, and by ongoing loss of cardiomyocytes through necrosis or apoptosis. Chronic treatment with beta blockers in patients with HF and in animals with experimentally induced HF has been shown to reverse, prevent, or, at the least, arrest many, if not all, of these adverse processes. Beta blockers improve function of the failing LV, prevent or reverse progressive LV dilation, chamber sphericity, and hypertrophy, and consequently have positive impact on cardiac remodeling. Beta blockers also reduce heart rate and LV wall stress, leading to reduced myocardial oxygen consumption, a clear benefit to the failing heart. Beta blockers can also improve the intrinsic contractile function of cardiomyocytes and have also been shown to improve myocardial energetics in HF, possibly through desirable changes in substrate utilization. Recent studies from our laboratories have also shown that beta blockers can attenuate cardiomyocyte apoptosis in HF. These benefits provide strong reinforcement to the clinical findings that beta blockers are highly beneficial for the management of patients with chronic HF and, when properly used, afford unequivocal reductions in mortality and morbidity in this patient population. At present, there is general agreement that increased cardiac sympathetic drive occurs in HF and may potentially be an important contributor to the progression of LV dysfunction and chamber remodeling that is characteristic of this disease state. Experimental studies in animal models of HF as well as clinical studies in patients with HF have suggested that chronic therapy with beta blockade is effective in preventing the progression of LV dysfunction and remodeling, the latter evidenced by reversal and/or prevention of progressive LV dilation and chamber sphericity. Results of recent multicenter clinical trials support these findings and have made it abundantly clear that long-term therapy with beta blockade inhibits clinical progression and has a major impact on mortality and morbidity in patients with HF that is at least as favorable, if not better, than that observed with angiotensin-converting enzyme (ACE) inhibitors. Beta blockers improve mortality and morbidity in HF and also improve LV ejection fraction (EF), a beneficial feature that, until recently, has only been attributed to positive inotropic agents.


Cognitive and neuropsychiatric impairment in cerebral radionecrosis patients after radiotherapy of nasopharyngeal carcinoma.
We sought to characterize the cognitive function and neuropsychiatric symptoms in cerebral radionecrosis (CRN) patients who have received conformal radiation for nasopharyngeal carcinoma. A total of 40 patients treated with radiotherapy (RT) that developed CRN (RT + CRN), 40 patients treated with radiotherapy that did not have CRN (RT-No-CRN), and 36 newly diagnosed untreated nasopharyngeal carcinoma patients (No-RT) were recruited. The cognitive function and neuropsychiatric symptoms were evaluated with Montreal cognitive assessment (MoCA), the mini-mental state examination (MMSE), activity of daily living scale (ADL), neuropsychiatric inventory (NPI), Hamilton depression scale (HAMD) and Hamilton anxiety scale (HAMA). The RT + CRN group had the lowest mean MMSE, MoCA and ADL scores, while highest mean NPI, HAMD and HAMA scores among the three patient groups (P < 0.05). Thirty (75%) of the RT + CRN patients were deemed cognitively impaired by the MoCA compared with 9 (22.5%) by the MMSE (χ(2) = 22.064; P < 0.001). Eighty-two percents of subject in RT + CRN group experienced neuropsychiatric symptoms within the past 4 weeks. Irritability, anxiety, depression and agitation in the RT + CRN group were of the most significantly frequent among the 3 groups. The CRN patients generally have manifestations in cognitive and psychological impairment, which have their typical characteristics, and should be considered in CRN treatment and rehabilitation. The MoCA classifies more CRN patients as cognitively impaired than the MMSE, justifying further studies of the MoCA as an appropriate screen for CRN.


Colon cancer screening with CT colonography: logistics, cost-effectiveness, efficiency and progress.
Colorectal cancer (CRC) incidence and mortality can be significantly reduced by population screening. Several different screening methods are currently in use, and this review focuses specifically on the imaging technique computed tomographic colonography (CTC). The challenges and logistics of CTC screening, as well as the importance of test accuracy, uptake, quality assurance and cost-effectiveness will be discussed. With comparable advanced adenoma detection rates to colonoscopy (the most commonly used whole-colon investigation), CTC is a less-invasive alternative, requiring less laxative, and with the potential benefit that it permits assessment of extra colonic structures. Three large-scale European trials have contributed valuable evidence supporting the use of CTC in population screening, and highlight the importance of selecting appropriate clinical management pathways based on initial CTC findings. Future research into CTC-screening will likely focus on radiologist training and CTC quality assurance, with identification of evidence-based key performance indicators that are associated with clinically-relevant outcomes such as the incidence of post-test interval cancers (CRC occurring after a presumed negative CTC). In comparison to other CRC screening techniques, CTC offers a safe and accurate option that is particularly useful when colonoscopy is contraindicated. Forthcoming cost-effectiveness analyses which evaluate referral thresholds, the impact of extra-colonic findings and real-world uptake will provide useful information regarding the feasibility of future CTC population screening.


Ensembled Feature based Multi-Label ECG Arrhythmia Classification.
Arrhythmia is one of the major contributors to sudden cardiac death. Compared to single-label arrhythmia classification, multi-label classification provides the advantage of simultaneous detection of different cardiac ailments. Existing multi-label approaches employ deep learning models, which have several limitations, e.g., data dependency, overfitting, complexity, and lack of interpretability. In this work, we propose a multi-label classification framework with ensembled hand-crafted features added with label powerset, which better preserves the correlation between classes. Experimentation with CPSC 2018 database shows that the proposed model provides accuracy and F1-score of 88.52% and 88.45% for single-label data and 88.11% and 86.32% for multi-label data, respectively. The proposed method improves individual class performance for some important diseases compared to the existing multi-label state-of-the-art methods.Clinical relevance- Early detection of life-threatening multi-label ECG patterns consisting of atrial fibrillation, atrioventricular block, and right bundle branch block with high accuracy can reduce the sudden cardiac death rate.


Precisely modeling zero-inflated count phenotype for rare variants.
Count data with excessive zeros are increasingly ubiquitous in genetic association studies, such as neuritic plaques in brain pathology for Alzheimer's disease. Here, we developed gene-based association tests to model such data by a mixture of two distributions, one for the structural zeros contributed by the Binomial distribution, and the other for the counts from the Poisson distribution. We derived the score statistics of the corresponding parameter of the rare variants in the zero-inflated Poisson regression model, and then constructed burden (ZIP-b) and kernel (ZIP-k) tests for the association tests. We evaluated omnibus tests that combined both ZIP-b and ZIP-k tests. Through simulated sequence data, we illustrated the potential power gain of our proposed method over a two-stage method that analyzes binary and non-zero continuous data separately for both burden and kernel tests. The ZIP burden test outperformed the kernel test as expected in all scenarios except for the scenario of variants with a mixture of directions in the genetic effects. We further demonstrated its applications to analyses of the neuritic plaque data in the ROSMAP cohort. We expect our proposed test to be useful in practice as more powerful than or complementary to the two-stage method.


Summer hypoxia in the northern Gulf of Mexico and its prediction from 1978 to 1995.
An 18-year monitoring record (1978-1995) of dissolved oxygen within a region having hypoxia (dissolved oxygen less than 2 mgl(-1)) in the bottom layer was examined to describe seasonal and annual trends. The monitoring location was near or within a well-described summer hypoxic zone whose size has been up to 20,000 km(2). The monitoring data were used to hindcast the size of the hypoxic zone for before consistent shelfwide surveys started, and to predict it for 1989, when a complete shelfwide survey was not made. The concentration of total Kjeldahl nitrogen (TKN) in surface waters and concentration of bottom water oxygen were directly related, as anticipated if organic loading from surface to bottom was from in situ processes. The TKN data were used to develop a predictive relationship that suggested there was no substantial hypoxia before the 1970s, which was before nitrate flux from the Mississippi River to the Gulf of Mexico began to rise. The peak frequency in monthly hypoxic events is two to three months after both the spring maximum in discharge and nitrate loading of the Mississippi River. These results support the conclusion that persistent, large-sized summer hypoxia is a recently-developed phenomenon that began in the 1970s or early 1980s.


Low expression of LncRNA AFAP1-AS1 inhibits proliferation and promotes apoptosis of non-small cell lung cancer cells through inhibiting wnt signaling pathway.
To detect the effects of long non-coding ribonucleic acid (lncRNA) actin filament-associated protein 1-antisense RNA1 (AFAP1-AS1) on the proliferation and apoptosis of non-small cell lung cancer (NSCLC) A549 cells and its mechanism. 1) The expression of lncRNA AFAP1-AS1 in NSCLC A549 cells was detected via quantitative reverse transcription-polymerase chain reaction (qRT-PCR). 2) The changes in proliferation and apoptosis of A549 cells after low expression of lncRNA AFAP1-AS1 were detected using cell counting kit-8 (CCK-8) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays. 3) The changes in Wnt signaling pathway proteins in A549 cells after low expression of lncRNA AFAP1-AS1 were detected using Western blotting. 1) The expression of lncRNA AFAP1-AS1 rose in A549 cells (P<0.01). 2) After low expression of lncRNA AFAP1-AS1, the growth of A549 cells was inhibited, and apoptosis was promoted. 3) After low expression of lncRNA AFAP1-AS1, the mRNA and protein expressions of glycogen synthase kinase (GSK) and β-catenin declined (P<0.05). Lowly-expressed AFAP1-AS1 inhibits the proliferation and promotes the apoptosis of NSCLC A549 cells via inhibiting the Wnt signaling pathway.


Use of physiologic reasoning to diagnose and manage shock States.
Shock states are defined by stereotypic changes in well-known physiologic parameters. While these well-known changes provide a convenient entry point into further evaluation of patients in shock or at risk for shock, use of such physiologic evaluation is not commonly seen in clinical medicine. A formal description of physiologic reasoning in the diagnosis of shock states is presented in this paper. Included with this conceptual framework is a discussion of key tests or findings that can be used to differentiate between possible diagnoses, and the pairing of treatment strategies to distinct classes of physiologic abnormalities. It is hoped that the methodology presented here will demonstrate the primacy of physiologic reasoning in the diagnosis and treatment of hemodynamic instability. Advantages of this method are speed and accuracy, efficient use of resources, and mitigation against sources of medical errors.


Transfer function of multimode fiber links using an electric field propagation model: Application to Radio over Fibre Systems.
We present a closed-form expression for the evaluation of the transfer function of a multimode fiber (MMF) link based on the electric field propagation model. After validating the result we investigate the potential for broadband transmission in regions far from baseband. We find that MMFs offer the potential for broadband ROF transmission in the microwave and millimetre wave regions in short and middle reach distances.


IL-26 Confers Proinflammatory Properties to Extracellular DNA.
In physiological conditions, self-DNA released by dying cells is not detected by intracellular DNA sensors. In chronic inflammatory disorders, unabated inflammation has been associated with a break in innate immune tolerance to self-DNA. However, extracellular DNA has to complex with DNA-binding molecules to gain access to intracellular DNA sensors. IL-26 is a member of the IL-10 cytokine family, overexpressed in numerous chronic inflammatory diseases, in which biological activity remains unclear. We demonstrate in this study that IL-26 binds to genomic DNA, mitochondrial DNA, and neutrophil extracellular traps, and shuttles them in the cytosol of human myeloid cells. As a consequence, IL-26 allows extracellular DNA to trigger proinflammatory cytokine secretion by monocytes, in a STING- and inflammasome-dependent manner. Supporting these biological properties, IL-10-based modeling predicts two DNA-binding domains, two amphipathic helices, and an in-plane membrane anchor in IL-26, which are structural features of cationic amphipathic cell-penetrating peptides. In line with these properties, patients with active autoantibody-associated vasculitis, a chronic relapsing autoimmune inflammatory disease associated with extensive cell death, exhibit high levels of both circulating IL-26 and IL-26-DNA complexes. Moreover, in patients with crescentic glomerulonephritis, IL-26 is expressed by renal arterial smooth muscle cells and deposits in necrotizing lesions. Accordingly, human primary smooth cells secrete IL-26 in response to proinflammatory cytokines. In conclusion, IL-26 is a unique cationic protein more similar to a soluble pattern recognition receptor than to conventional cytokines. IL-26 expressed in inflammatory lesions confers proinflammatory properties to DNA released by dying cells, setting up a positive amplification loop between extensive cell death and unabated inflammation.


Interventions for anal canal intraepithelial neoplasia.
Anal canal intraepithelial neoplasia (AIN) is a pre-malignant condition of the anal canal transitional epithelium that is associated with human papillomavirus (HPV) infection. The incidence and prevalence of AIN and anal cancer are increasing rapidly in HIV-positive men who have sex with men (MSM). Other groups like HIV-negative MSM, immunosuppressed patients and people affected by other HPV diseases like genital warts and cervical intraepithelial neoplasia (CIN) may also develop AIN. The condition is complicated by its multicentric and multifocal nature and high rates of relapse and morbidity. Targeted excisions using ablative treatments such as cautery, infrared coagulation (IRC) and cryotherapy have been used as first-line therapeutic strategies, and there are many other options. There is no consensus about the optimal management of AIN. To evaluate the effects of therapeutic interventions for anal canal intraepithelial neoplasia (AIN). We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 4), MEDLINE and EMBASE (to October 2011). We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of included studies, and contacted experts in the field and manufacturers of any AIN and HPV-specific treatments. Randomized controlled trials (RCTs) that assessed any type of intervention for AIN. Two review authors independently abstracted data and assessed risk of bias. If it was possible, the data were synthesised in a meta-analysis. We found only one RCT, which included 53 patients, that met our inclusion criteria. This trial reported data on imiquimod versus placebo. There was no statistically significant difference in the risk of disease cure but there was a trend for imiquimod to downgrade the AIN to a low-risk stage. The lack of statistical power of the trial may be due to the small number of patients in each group. The risk of bias was estimated as moderate. The included trial failed to demonstrate any statistically significant efficacy of imiquimod in the management of anal intraepithelial neoplasia (AIN). The absence of reliable evidence for any of the interventions used in AIN precludes any definitive guidance or recommendations for clinical practice. Prospective cohort studies and retrospective studies have not been included in this review as they are considered to provide lower quality evidence. Well designed RCTs are needed.


Combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and actinomycin D induces apoptosis even in TRAIL-resistant human pancreatic cancer cells.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a novel member of the tumor necrosis factor superfamily of cytokines that induces cell death by apoptosis. TRAIL has been shown to be effective in almost two-thirds of solid tumors tested thus far, but its effect on pancreatic cancer cells is unknown. We tested the effect of TRAIL on seven human pancreatic cancer cell lines (HPAF, Panc1, Miapaca2, Bxpc3, Panc89, SW979, and Aspc1) in vitro. Of these cell lines, all but Aspc1 showed a significant dose-dependent increase in apoptosis. The apoptotic rate, as detected by a terminal deoxynucleotidyl transferase-mediated nick end labeling assay, was highest in Bxpc3 (71.5%), followed by HPAF (38.0%), Miapaca2 (24.9%), Panc1 (16.1%), Panc89 (15.8%), SW979 (13.9%), and Aspc1 (5.2%). Multiple treatments were more effective than a single treatment and caused a sustained and profound cell death in all but Aspc1 cells. There was no correlation between the effect of TRAIL and the differentiation grade of the cell lines, p53 mutation, or bcl-2 or bax expression. The resistance of Aspc1 cells to TRAIL was not related to the lack of TRAIL receptors. The combination of actinomycin D and TRAIL induced an almost complete lysis of Aspc1 cells, whereas actinomycin D alone had no effect on cell survival but inhibited the expression of the Flice inhibitory protein, which is assumed to play a role in the apoptotic pathway of TRAIL. Thus, the combination of actinomycin D and TRAIL appears to be a promising approach for the therapy of pancreatic cancers resistant to TRAIL.


Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes.
The advent and refinement of sequencing technologies has resulted in a decrease in both the cost and time needed to generate data on the entire sequence of the human genome. This has increased the accessibility of using whole-genome sequencing and whole-exome sequencing approaches for analysis in both the research and clinical contexts. The expectation is that more services based on these and other high-throughput technologies will become available to patients and the wider population. Some authors predict that sequencing will be performed once in a lifetime, namely, shortly after birth. The Public and Professional Policy Committee of the European Society of Human Genetics, the Human Genome Organisation Committee on Ethics, Law and Society, the PHG Foundation and the P3G International Paediatric Platform address herein the important issues and challenges surrounding the potential use of sequencing technologies in publicly funded newborn screening (NBS) programmes. This statement presents the relevant issues and culminates in a set of recommendations to help inform and guide scientists and clinicians, as well as policy makers regarding the necessary considerations for the use of genome sequencing technologies and approaches in NBS programmes. The primary objective of NBS should be the targeted analysis and identification of gene variants conferring a high risk of preventable or treatable conditions, for which treatment has to start in the newborn period or in early childhood.


A new neosuchian with Asian affinities from the Jurassic of northeastern Brazil.
Phylogenetic relationships near the origin of extant crocodylians are weakly supported, and this lack of resolution makes for poor estimates of taxonomic and morphological diversity. Previously known taxa are found throughout the Cretaceous in Laurasia and at a few sites from Brazil, Australia, and northern Africa. Here, we report Batrachomimus pastosbonensis gen. et sp. nov. from the Late Jurassic of northeastern Brazil, which is deeply nested within Neosuchia and associated to the Cretaceous Asian paralligatorids. The new taxon predates all other members of Paralligatoridae and its immediate sister group (including Eusuchia) by 30 million years. A nearly complete skull, osteoderms, and limb bones were recovered, and autapomorphies of B. pastosbonensis include a scalloped lateral margin of the rostrum in dorsal view, unsculpted alveolar margin at the caudalmost portion of the maxilla, blunt lateral prongs on the jugal at the base of the postorbital bar, hourglass shaped choanae, and pterygoid choanal septum extended between the palatal shelves of the palatines. The crocodyloid-like skull proportions and the slender, conical teeth suggest an amphibious and piscivorous life history to this 1 m long animal.


Phenomenological Transparency.
Translucent objects such as fog, clouds, smoke, glass, ice, and liquids are pervasive in cinematic environments because they frame scenes in depth and create visually-compelling shots. Unfortunately, they are hard to render in real-time and have thus previously been rendered poorly compared to opaque surfaces. This paper introduces the first model for a real-time rasterization algorithm that can simultaneously approximate the following transparency phenomena: wavelength-varying ("colored") transmission, translucent colored shadows, caustics, volumetric light and shadowing, partial coverage, diffusion, and refraction. All render efficiently with order-independent draw calls and low bandwidth. We include source code.


"It Would've Been Nice if They Interpreted the Data a Little Bit. It Didn't Really Say Much, and It Didn't Really Help Us.": A Qualitative Study of VA Health System Evidence Needs.
Patient health outcomes improve when learning health care systems use evidence to implement promising services and allocate resources effectively. Here, we examine the unique environment in which Veterans Health Administration (VHA) leadership use evidence and the facilitators and barriers to using evidence synthesis products in decision-making. We end by describing the steps researchers can take to better support the needs of health system leadership. We conducted 20 semistructured phone interviews with individuals in VHA leadership positions. We used an inductive approach to identify themes observed across key informant interviews. Key informants identified several factors that fostered the use of evidence including, timeliness, lack of bias, flexible approaches, and concise reports with a clear bottom line. Barriers included lack of relevant evidence and lack of information on how to translate evidence into practice, resistance to change among providers and within the larger health system, and political pressures to implement therapies or technologies with little evidence or uncertainty. Researchers can foster evidence uptake by developing a review scope and key questions that are important to multiple stakeholders, including frontline clinicians and health system leadership. The VHA's evidence needs resemble other health systems, but evidence synthesis products should include a translational component to enhance implementation. Resistance to change and political pressures can further hinder the uptake of evidence within VHA.


Morphological changes in frog pronephric cell surfaces after transformation by herpes virus.
A scanning electron-microscope study has established that there are major modifications in the surface membranes of malignant cells transformed from the pronephric kidney of the frog. Tumours were induced in vivo after exposure of embryos Lucké Herpes virus. A pronephric cell line from normal embryos and 3 tumour cell lines derived from experimentally induced adenocarcinomas of the pronephros were observed. The normal embryonic kidney cells have their surfaces covered with long fingerlike microvilli throughout the cell cycle. In contrast, the surface of the pronephric tumour cells are mainly covered by multiple, ruffled or parallel straight microridges and short, stubby microvilli. These comparisons were made on cells subject to similar culture conditions. The topographic changes in the tumour cells are considered significant since the characteristic microridges and stubby villi were consistently found in all 3 pronephric tumour lines.


Measuring Peak Inspiratory Flow in Patients with Chronic Obstructive Pulmonary Disease.
Dry powder inhalers (DPIs) are breath actuated, and patients using DPIs need to generate an optimal inspiratory flow during the inhalation maneuver for effective drug delivery to the lungs. However, practical and standardized recommendations for measuring peak inspiratory flow (PIF)-a potential indicator for effective DPI use in chronic obstructive pulmonary disease (COPD)-are lacking. To evaluate recommended PIF assessment approaches, we reviewed the Instructions for Use of the In-Check™ DIAL and the prescribing information for eight DPIs approved for use in the treatment of COPD in the United States. To evaluate applied PIF assessment approaches, we conducted a PubMed search from inception to August 31, 2021, for reports of clinical and real-life studies where PIF was measured using the In-Check™ DIAL or through a DPI in patients with COPD. Evaluation of collective sources, including 47 applicable studies, showed that instructions related to the positioning of the patient with their DPI, instructions for exhalation before the inhalation maneuver, the inhalation maneuver itself, and post-inhalation breath-hold times varied, and in many instances, appeared vague and/or incomplete. We observed considerable variation in how PIF was measured in clinical and real-life studies, underscoring the need for a standardized method of PIF measurement. Standardization of technique will facilitate comparisons among studies. Based on these findings and our clinical and research experience, we propose specific recommendations for PIF measurement to standardize the process and better ensure accurate and reliable PIF values in clinical trials and in daily clinical practice.


A study of gibberellin homeostasis and cryptochrome-mediated blue light inhibition of hypocotyl elongation.
Cryptochromes mediate blue light-dependent photomorphogenic responses, such as inhibition of hypocotyl elongation. To investigate the underlying mechanism, we analyzed a genetic suppressor, scc7-D (suppressors of cry1cry2), which suppressed the long-hypocotyl phenotype of the cry1cry2 (cryptochrome1/cryptochrome2) mutant in a light-dependent but wavelength-independent manner. scc7-D is a gain-of-expression allele of the GA2ox8 gene encoding a gibberellin (GA)-inactivating enzyme, GA 2-oxidase. Although scc7-D is hypersensitive to light, transgenic seedlings expressing GA2ox at a level higher than scc7-D showed a constitutive photomorphogenic phenotype, confirming a general role of GA2ox and GA in the suppression of hypocotyl elongation. Prompted by this result, we investigated blue light regulation of mRNA expression of the GA metabolic and catabolic genes. We demonstrated that cryptochromes are required for the blue light regulation of GA2ox1, GA20ox1, and GA3ox1 expression in transient induction, continuous illumination, and photoperiodic conditions. The kinetics of cryptochrome induction of GA2ox1 expression and cryptochrome suppression of GA20ox1 or GA3ox1 expression correlate with the cryptochrome-dependent transient reduction of GA(4) in etiolated wild-type seedlings exposed to blue light. Therefore we propose that in deetiolating seedlings, cryptochromes mediate blue light regulation of GA catabolic/metabolic genes, which affect GA levels and hypocotyl elongation. Surprisingly, no significant change in the GA(4) content was detected in the whole shoot samples of the wild-type or cry1cry2 seedlings grown in the dark or continuous blue light, suggesting that cryptochromes may also regulate GA responsiveness and/or trigger cell- or tissue-specific changes of the level of bioactive GAs.


Population dependent Fourier decomposition of fitness landscapes over recombination spaces: evolvability of complex characters.
The effect of recombination on genotypes can be represented in the form of P-structures, i.e., a map from the set of pairs of genotypes to the power set of genotypes. The interpretation is that the P-structure maps the pair of parental genotypes to the set of recombinant genotypes which result from the recombination of the parental genotypes. A recombination fitness landscape is then a function from the genotypes in a P-structure to the real numbers. In previous papers we have shown that the eigenfunctions of (a matrix associated with) the P-structure provide a basis for the Fourier decomposition of arbitrary recombination landscapes. Here we generalize this framework to include the effect of genotype frequencies, assuming linkage equilibrium. We find that the autocorrelation of the eigenfunctions of the population-weighted P-structure is independent of the population composition. As a consequence we can directly compare the performance of mutation and recombination operators by comparing the autocorrelations on the finite set of elementary landscapes. This comparison suggests that point mutation is a superior search strategy on landscapes with a low order and a moderate order of interaction p < n/3 (n is the number of loci). For more complex landscapes 1-point recombination is superior to both mutation and uniform recombination, but only if the distance among the interacting loci (defining length) is minimal. Furthermore we find that the autocorrelation on any landscape is increasing as the distribution of genotypes becomes more extreme, i.e., if the population occupies a location close to the boundary of the frequency simplex. Landscapes are smoother the more biased the distribution of genotype frequencies is. We suggest that this result explains the paradox that there is little epistatic interaction for quantitative traits detected in natural populations if one uses variance decomposition methods while there is evidence for strong interactions in molecular mapping studies for quantitative trait loci.


How easy is it for young people to obtain cigarettes, and do test sales by trading standards have any effect? A survey of two schools in Gateshead.
Smoking prevalence among young people continues to rise and cigarettes are easily available from many shops. Test sales are used by trading standards departments to try to reduce under-age sales, but it is not known whether this has any real impact on cigarette purchase and consumption. This study aims to evaluate the impact of test sales on purchase and consumption of cigarettes by young people. A survey of two schools in Gateshead, one in the intervention area and one acting as a control was carried out. A series of test sales were targeted to shops within 1.5 km of the intervention school. A questionnaire was administered in both schools among year 10 pupils, age 14-15 years, prior to the intervention and again 1 year later. The outcomes measured were number of successful test sales, reported availability of cigarettes and change in smoking prevalence following the intervention. Some 224 pupils from both schools were surveyed in 1995 and 163 pupils from the new cohort of year 10 pupils in 1996. Prior to the intervention, the levels of regular smoking in the intervention school were 39% for girls and 26% for boys. In the control school these levels were 24% and 14%, respectively. The intervention by trading standards resulted in no purchases and hence no prosecutions, but children reported being able to buy cigarettes with ease from the nearby shops; only three (2.5%) reported sales refused in 1995 and five (5.8%) in 1996. Not surprisingly there was no significant change in smoking prevalence in either school in 1996. This study suggests that test sales may not be effective in modifying cigarette availability to young people and that they are not a reliable measure of access to cigarettes by children.


Anomalous hydrodynamical dispersion and the transport with multiple families of paths in porous media.
We investigate a family of probability distributions that shows anomalous hydrodynamic dispersion, by solving a particular class of coupled generalized master equations. The Fourier-Laplace solution is obtained analytically in terms of the matrix Green function method; then the Coats-Smith concentration profile is revisited in a particular case. Two models of disorder are worked out explicitly, and the mean current is asymptotically calculated. We present an approximation method to calculate the first passage time distribution for this stochastic transport process, and as an example an exact Markovian result is worked out; scaling results are also shown. We discuss the comparison with other different methods to work out complex diffusion phenomena in the presence of disordered multiple transport paths. Extensions when the models are nondiffusive can also be solved in the Fourier-Laplace representation.


Determination of sexual problems of Turkish patients receiving gynecologic cancer treatment: a cross-sectional study.
The present study aimed to determine the prevalence and types of sexual problems of Turkish patients receiving gynecologic cancer treatment. A cross-sectional convenience sample of 168 women completed the Index of Female Sexual Function (IFSF) and a Patient Identification Form in a hospital in Ankara, Turkey. Mean IFSF scores of the patients were low (15.7±5.72, out of a possible 45), indicating high rates of sexual problems. Women frequently reported problems with dyspareunia (97.1%), vaginal dryness (97.6%), decreased sexual desire (91.1%), and difficulties of sexual arousal (92.9%) related with the cancer treatment process. They reported increased sexual problems following the period of treatment as compared to before treatment (p<0.05). Sexual dysfunction was associated with low educational and income levels, advanced age, TAH-BSO-LND surgery (total abdominal hysterectomy-bilateral salphingoopherectomy- lymph node dissection), experiencing side effects of chemotherapy, receiving chemotherapy in addition to surgery and radiotherapy (CT+RT+Surgery), and having a large number of chemotherapy cycles (p<0.05). Patients hoped for and expected counseling from healthcare professionals about their sexual functioning in relation to cancer treatments. Nurses and physicians can help to improve the overall quality of life for gynecologic cancer patients through sexual counseling.


Profile of belatacept and its potential role in prevention of graft rejection following renal transplantation.
The last several decades have witnessed a substantial decrease in the incidence of acute allograft rejection following kidney transplantation, although commensurate improvements in long-term graft function have not been realized. As a result, the primary focus of new immunosuppressive drug development has expanded to include ease of use and improved side effect profile, including reduced nephrotoxicity, in addition to the more traditional goal of improved short-term outcomes. A number of novel drugs are currently under investigation in Phase I, II, or III clinical trials, primarily to replace the nephrotoxic but highly effective calcineurin inhibitors. Belatacept is a humanized antibody that inhibits T cell costimulation and has shown encouraging results in multiple Phase II and III trials. This article reviews the mechanism of action of belatacept, as well as published and preliminary results of the Phase I-III clinical trials involving this novel immunosuppressive agent.


Assessment of domain interactions in the fourteenth round of the Critical Assessment of Structure Prediction (CASP14).
The high accuracy of some CASP14 models at the domain level prompted a more detailed evaluation of structure predictions on whole targets. For the first time in critical assessment of structure prediction (CASP), we evaluated accuracy of difficult domain assembly in models submitted for multidomain targets where the community predicted individual evaluation units (EUs) with greater accuracy than full-length targets. Ten proteins with domain interactions that did not show evidence of conformational change and were not involved in significant oligomeric contacts were chosen as targets for the domain interaction assessment. Groups were ranked using complementary interaction scores (F1, QS score, and Jaccard coefficient), and their predictions were evaluated for their ability to correctly model inter-domain interfaces and overall protein folds. Target performance was broadly grouped into two clusters. The first consisted primarily of targets containing two EUs wherein predictors more broadly predicted domain positioning and interfacial contacts correctly. The other consisted of complex two-EU and three-EU targets where few predictors performed well. The highest ranked predictor, AlphaFold2, produced high-accuracy models on eight out of 10 targets. Their interdomain scores on three of these targets were significantly higher than all other groups and were responsible for their overall outperformance in the category. We further highlight the performance of AlphaFold2 and the next best group, BAKER-experimental on several interesting targets.


Laterally wedged insoles in knee osteoarthritis: do biomechanical effects decline after one month of wear?
This study aimed to determine whether the effect of laterally wedged insoles on the adduction moment in knee osteoarthritis (OA) declined after one month of wear, and whether higher reported use of insoles was associated with a reduced effect on the adduction moment at one month. Twenty people with medial compartment OA underwent gait analysis in their own shoes wearing i) no insoles and; ii) insoles wedged laterally 5 degrees in random order. Testing occurred at baseline and after one month of use of the insoles. Participants recorded daily use of insoles in a log-book. Outcomes were the first and second peak external knee adduction moment and the adduction angular impulse, compared across conditions and time with repeated measures general linear models. Correlations were obtained between total insole use and change in gait parameters with used insoles at one month, and change scores were compared between high and low users of insoles using general linear models. There was a significant main effect for condition, whereby insoles significantly reduced the adduction moment (all p < 0.001). However there was no significant main effect for time, nor was an interaction effect evident. No significant associations were observed between total insole use and change in gait parameters with used insoles at one month, nor was there a difference in effectiveness of insoles between high and low users of the insoles at this time. Effects of laterally wedged insoles on the adduction moment do not appear to decline after one month of continuous use, suggesting that significant wedge degradation does not occur over the short-term.


A spatial evaluation of historic iron mining impacts on current impaired waters in Lake Superior's Mesabi Range.
This paper examines the water quality legacies of historic and current iron mining in the Mesabi Range, the most productive iron range in the history of North America, producing more than 42% of the world's iron ore in the 1950s. Between 1893 and 2016, 3.5 × 109 t of iron ore were shipped from the Mesabi Range to steel plants throughout the world. We map historic sites and quantities of iron mining, ore processing, water use, and tailings deposition within subwatershed boundaries. We then map the locations of impaired lakes within HUC-12 subwatershed boundaries within the Mesabi Range, using government datasets created for US federal Clean Water Act reporting. Comparing watersheds with and without historic mining activity, watersheds with historic mining activity currently contain a greater percentage of impaired lakes than control watersheds within the same range. These results suggest that historic iron ore mining and processing in the Mesabi Range affected water quality on a landscape scale, and these legacies persist long after the mines have closed. This paper outlines a novel spatial approach that land managers and policy makers can apply to other landscapes to assess the effects of past mining activity on watershed health.


Mammalian telomeric DNA suppresses endotoxin-induced uveitis.
Telomeric regions of mammalian chromosomes contain suppressive TTAGGG motifs that inhibit several proinflammatory and Th1-biased immune responses. Synthetic oligodeoxynucleotides (ODN) expressing suppressive motifs can reproduce the down-regulatory activity of mammalian telomeric repeats and have proven effective in the prevention and treatment of several autoimmune and autoinflammatory diseases. Endotoxin-induced uveitis (EIU) is an established animal model of acute ocular inflammation induced by LPS administration. Augmented expression of proinflammatory cytokines/chemokines such as TNFalpha, IL-6, and MCP1 and bactericidal nitric oxide production mediated by LPS contribute to the development of EIU. Suppressing these mediators using agents that are devoid of undesirable systemic side effects may help prevent the development of EIU. This study demonstrates the selective down-regulatory role of suppressive ODN after (i) local or (ii) systemic treatment in EIU-induced rabbits and mice. Our results indicate that suppressive ODN down-regulate at both the transcript and protein levels of several proinflammatory cytokines and chemokines as well as nitric oxide and co-stimulatory surface marker molecules when administrated prior to, simultaneously with, or even after LPS challenge, thereby significantly reducing ocular inflammation in both rabbit and mouse eyes. These findings strongly suggest that suppressive ODN is a potent candidate for the prevention of uveitis and could be applied as a novel DNA-based immunoregulatory agent to control other autoimmune or autoinflammatory diseases.


Emergency Medicine Evaluation of Community-Acquired Pneumonia: History, Examination, Imaging and Laboratory Assessment, and Risk Scores.
Pneumonia is a common infection, accounting for approximately one million hospitalizations in the United States annually. This potentially life-threatening disease is commonly diagnosed based on history, physical examination, and chest radiograph. To investigate emergency medicine evaluation of community-acquired pneumonia including history, physical examination, imaging, and the use of risk scores in patient assessment. Pneumonia is the number one cause of death from infectious disease. The condition is broken into several categories, the most common being community-acquired pneumonia. Diagnosis centers on history, physical examination, and chest radiograph. However, all are unreliable when used alone, and misdiagnosis occurs in up to one-third of patients. Chest radiograph has a sensitivity of 46-77%, and biomarkers including white blood cell count, procalcitonin, and C-reactive protein provide little benefit in diagnosis. Biomarkers may assist admitting teams, but require further study for use in the emergency department. Ultrasound has shown utility in correctly identifying pneumonia. Clinical gestalt demonstrates greater ability to diagnose pneumonia. Clinical scores including Pneumonia Severity Index (PSI); Confusion, blood Urea nitrogen, Respiratory rate, Blood pressure, age 65 score (CURB-65); and several others may be helpful for disposition, but should supplement, not replace, clinical judgment. Patient socioeconomic status must be considered in disposition decisions. The diagnosis of pneumonia requires clinical gestalt using a combination of history and physical examination. Chest radiograph may be negative, particularly in patients presenting early in disease course and elderly patients. Clinical scores can supplement clinical gestalt and assist in disposition when used appropriately.


Effect of laparoscopic gastrectomy on compliance with adjuvant chemotherapy in patients with gastric cancer.
This study was designed to investigate the effect of laparoscopic gastrectomy on adjuvant chemotherapy in patients with gastric cancer.Patients with gastric cancer who underwent radical gastrectomy at our institution from January 2008 to January 2015 with R0 resection, as determined by a pathological examination, were included in this study. According to the surgical approach, patients were divided into the laparoscopic gastrectomy (LG) group and open gastrectomy (OG) group. Short-term and long-term outcomes were compared between the 2 groups.Of the 206 patients enrolled in the study, 114 patients were included in the LG group and 92 patients were included in the OG group. There was no significant difference in patients' general data, including age, sex, medical comorbidities, and pathological staging, between the 2 groups. However, patients in the LG group had less intraoperative blood loss, fewer postoperative complications, and a shorter hospital stay compared with patients in the OG group. There was no significant difference in the start time of adjuvant chemotherapy between the groups. However, compared with OG, LG had the following advantages: patients received more cycles of adjuvant chemotherapy, more patients received a full dose of on-schedule adjuvant chemotherapy, and more patients completed ≥75% of the planned dose. Long-term survival and disease-free survival rates were higher in the LG than in the OG.In summary, LG can improve compliance with adjuvant chemotherapy and long-term outcomes in patients with gastric cancer.


The post-prandial state and macrovascular disease: relevance to diabetes mellitus.
There is increasing evidence that the post-prandial state is an important contributing factor to the development of atherosclerosis. In non-diabetic subjects the atherosclerotic risk factors comprised in the categories of lipids, coagulation system and endothelial function may be adversely modified in the post-prandial phase. The generation of an oxidative stress may be the common pathway through which eating may induce these alterations. In diabetic patients these phenomena may be amplified by post-prandial hyperglycemia. There is a growing thought that diabetes is a cardiovascular disease.


Informatics and healthcare reform.
This paper examines how informatics has been applied in support of healthcare reform objectives, such as reducing the administrative burden on practitioners, reorienting health services to a community and client-based focus, and promoting intersectoral collaboration. It also discusses why some attempts have failed and resulting implications for the future.


Investigation of recombinant human insulin-like growth factor type I in thymus regeneration in the acute stage of experimental FIV infection in juvenile cats.
Thymus involvement and the development of thymic lesions in HIV-1 infection is hypothesized to suppress thymus function and limit T cell maturation and replenishment of the peripheral lymphoid pool. Therapeutic modulation to protect or enhance thymus function may therefore ameliorate peripheral lymphocytopenia and retard disease progression. Thymotrophic agents, such as insulin-like growth factor type I (IGF-I), may therefore represent adjunctive but important methods of treatment to protect or promote thymus function. The assessment of rhIGF-I in lentiviral infection and its impact on the thymus was performed using the feline immunodeficiency virus (FIV) model. Regeneration of the thymus in juvenile cats and amelioration of the thymic lesion after FIV infection was assessed by multiple measurements including thymic weight, stereologic analysis of the thymus cortex and medulla, histologic and immunohistologic analysis, quantitation of thymocyte and peripheral lymphocyte subsets, and quantitative competitive RT-PCR. Evidence of thymic cortical regeneration was observed in FIV-inoculated cats after 12 and 20 weeks of rhIGF-I treatment. Inflammation in the thymus was reduced during this period of treatment in this group of rhIGF-I/FIV-inoculated cats as evidenced by the reduced numbers of B cells detected. Viral replication rates in peripheral lymph nodes were not altered by rhIGF-I treatment and were decreased by 1 log in the thymus after 20 weeks of treatment. Peripheral blood CD4+ T cell counts also increased after 14 weeks of treatment. This suggests that rhIGF-I treatment can enhance thymus function and replenishment of the peripheral T cell pool.


BD Chloraprep™ ("2 % chlorhexidine with 70 % isopropyl alcohol") versus povidone iodine plus alcohol, for prevention of blood culture contamination at children: An investigator-initiated, open-label, single centre, randomized controlled trial.
One of the important problems that lower the diagnostic value of blood culture is contamination with skin organisms. The povidone-iodine, alcohol, and chlorhexidine gluconate alcohol are used for disinfection prior to blood sampling for culture. The investigator-initiated, open label, single centre, randomised trial compared blood culture contamination rates between two groups of patients in which using a povidone iodine skin-preparation process with the contamination rate for using "2 % chlorhexidine with 70 % isopropyl alcohol" skin-disinfection. The patients who required sampling for blood cultures were included in the study and study period was from 15 March 2023 to 15 July 2023. A total of 400 blood cultures were obtained during the study, including 133 in the study group and 267 in the control group. In the total blood cultures, 11.75 % (n = 47) had microorganism isolation. Among them 39 (9.75 %) were contaminants and 8 (2 %) of them were true pathogens. The contaminant microorganisms were as following; 34 coagulase-negative Staphylococci, 3 Micrococcus spp, and 2 Streptococci viridans. The blood culture contamination rate in the study group was 5.3 % (n = 7) and 12.0 % (n = 32) in the control group, and significantly lower in the study group (p = 0.033). There is no significant difference regarding skin related side effects between two groups. This study, showed that 2 % chlorhexidine gluconate in 70 % isopropyl alcohol is more efficacious in children than 10 % povidone-iodine preparations for disinfecting the skin prior to blood specimen collection for prevention of blood culture contamination.


Combinatorial functions of diverse histone methylations in Arabidopsis thaliana flowering time regulation.
Previous studies in Arabidopsis thaliana have identified several histone methylation enzymes, including Arabidopsis trithorax1 (ATX1)/set domain group 27 (SDG27), ATX2/SDG30, LSD1-LIKE1 (LDL1), LDL2, SDG8, SDG25, and curly leaf (CLF)/SDG1, as regulators of the key flowering repressor flowering locus C (FLC) and the florigen flowering locus T (FT). However, the combinatorial functions of these enzymes remain largely uninvestigated. Here, we investigated functional interplays of different histone methylation enzymes by studying higher order combinations of their corresponding gene mutants. We showed that H3K4me2/me3 and H3K36me3 depositions occur largely independently and that SDG8-mediated H3K36me3 overrides ATX1/ATX2-mediated H3K4me2/me3 or LDL1/LDL2-mediated H3K4 demethylation in regulating FLC expression and flowering time. By contrast, a reciprocal inhibition was observed between deposition of the active mark H3K4me2/me3 and/or H3K36me3 and deposition of the repressive mark H3K27me3 at both FLC and FT chromatin; and the double mutants sdg8 clf and sdg25 clf displayed enhanced early-flowering phenotypes of the respective single mutants. Collectively, our results provide important insights into the interactions of different types of histone methylation and enzymes in the regulation of FLC and FT expression in flowering time control.


Mutations in the tail domain of MYH3 contributes to atrial septal defect.
Atrial septal defect (ASD) is one of the most common congenital heart defects diagnosed in children. Sarcomeric genes has been attributed to ASD and knockdown of MYH3 functionally homologues gene in chick models indicated abnormal atrial septal development. Here, we report for the first time, a case-control study investigating the role of MYH3 among non-syndromic ASD patients in contributing to septal development. Four amplicons which will amplifies the 40 kb MYH3 were designed and amplified using long range-PCR. The amplicons were then sequenced using indexed paired-end libraries on the MiSeq platform. The STREGA guidelines were applied for planning and reporting. The non-synonymous c. 3574G>A (p.Ala1192Thr) [p = 0.001, OR = 2.30 (1.36-3.87)] located within the tail domain indicated a highly conserved protein region. The mutant model of c. 3574G>A (p.Ala1192Thr) showed high root mean square deviation (RMSD) values compared to the wild model. To our knowledge, this is the first study to provide compelling evidence on the pathogenesis of MYH3 variants towards ASD hence, suggesting the crucial role of non-synonymous variants in the tail domain of MYH3 towards atrial septal development. It is hoped that this gene can be used as panel for diagnosis of ASD in future.


Comprehensive analysis of the intracellular metabolism of antiretroviral nucleosides and nucleotides using liquid chromatography-tandem mass spectrometry and method improvement by using ultra performance liquid chromatography.
Nucleoside reverse transcriptase inhibitors (NRTIs) are a key class of drugs for the treatment of HIV infection. NRTIs are intracellularly phosphorylated to their active triphosphate metabolites and compete with endogenous deoxynucleotides (dNTP) for substrate binding. It is therefore important to analyze the intracellular concentrations of these compounds to understand drug efficacy and toxicity. To that purpose an analytical platform was developed that is capable of analyzing 8 NRTIs, 12 phosphorylated NRTIs and 4 dNTPs in small numbers of peripheral blood mononuclear cells, i.e. 1 × 10(6) cells. The platform consists of two liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods: a reversed-phase method for NRTIs using positive electrospray ionization (ESI) and an ion-pair LC-MS/MS method for the phosphorylated compounds using negative ESI. The methods use the same LC-MS system and column and changing from one method to the other only includes changing the mobile phase. The methods were partially validated, focussing on sensitivity, accuracy and precision. Successful transfer of the methods to ultra performance liquid chromatography (UPLC) led to a significant improvement of speed for the analysis of NRTIs and sensitivity for both NRTIs and phosphorylated NRTIs. The latter was demonstrated by the improved separation by UHPLC of dGTP vs. AZT-TP and ATP which made direct analysis of dGTP possible using the optimal MS/MS transition thereby significantly improving the detection limit of dGTP. Typically LLOQs observed for both the NRTIs and phosphorylated NRTIs were 1 nM, while the mean accuracy varied between 82 and 120% and inter- and intra-assay precision was generally <20%.


A Novel Force-Sensing Smart Textile: Inserting Silicone-Embedded FBG Sensors into a Knitted Undergarment.
A number of textile-based fiber optic sensors have recently been proposed for the continuous monitoring of vital signs. However, some of these sensors are likely unsuitable for conducting direct measurements on the torso as they lack elasticity and are inconvenient. This project provides a novel method for creating a force-sensing smart textile by inlaying four silicone-embedded fiber Bragg grating sensors into a knitted undergarment. The applied force was determined within 3 N after transferring the Bragg wavelength. The results show that the sensors embedded in the silicone membranes achieved enhanced sensitivity to force, as well as flexibility and softness. Additionally, by assessing the degree of FBG response to a range of standardized forces, the linearity (R2) between the shift in the Bragg wavelength and force was found to be above 0.95, with an ICC of 0.97, when tested on a soft surface. Furthermore, the real-time data acquisition could facilitate the adjustment and monitoring of force during the fitting processes, such as in bracing treatment for adolescent idiopathic scoliosis patients. Nevertheless, the optimal bracing pressure has not yet been standardized. This proposed method could help orthotists to adjust the tightness of brace straps and the location of padding in a more scientific and straightforward way. The output of this project could be further extended to determine ideal bracing pressure levels.


Cloning of mouse integrin alphaV cDNA and role of the alphaV-related matrix receptors in metanephric development.
Metanephrogenesis has been a long-standing model to study cell-matrix interactions. A number of adhesion molecules, including matrix receptors (i.e., integrins), are believed to be involved in such interactions. The integrins contain alpha and beta s ubunits and are present in various tissues in different heterodimeric forms. In this study, one of the members of the integrin superfamily, alphaV, was characterized, and its relevance in murine nephrogenesis was investigated. Mouse embryonic renal cDNA libraries were prepared and screened for alphaV, and multiple clones were isolated and sequenced. The deduced amino acid sequence of the alpha-v cDNA clones and hydropathic analysis revealed that it has a typical signal sequence and extracellular, transmembrane, and cytoplasmic domains, with multiple Ca2+ binding sites. No A(U)nA mRNA instability motifs were present. Conformational analysis revealed no rigid long-range-ordered structure in murine alphaV. The alphaV was expressed in the embryonic kidney at day 13 of the gestation, with a transcript size of approximately 7 kb. Its expression increased progressively during the later gestational stages and in the neonatal period. It was distributed in the epithelial elements of developing nephrons and was absent in the uninduced mesenchyme. In mature metanephroi, the expression was relatively high in the glomeruli and blood vessels, as compared to the tubules. Various heterodimeric associations of alphaV, i.e., with beta1, beta3, beta5, and beta6, were observed in metanephric tissues. Inclusion of alphaV-antisense-oligodeoxynucleotide or -antibody in metanephric culture induced dysmorphogenesis of the kidney with reduced population of the nephrons, disorganization of the ureteric bud branches, and reduction of mRNA and protein expressions of alphaV. The expressions of integrin beta3, beta5, and beta6 were unaltered. These findings suggest that the integrin alphaV is developmentally regulated, has a distinct spatio-temporal expression, and is relevant in the mammalian organogenesis.


Tetrazine-Based Ratiometric Nitric Oxide Sensor Identifies Endogenous Nitric Oxide in Atherosclerosis Plaques by Riding Macrophages as a Smart Vehicle.
Atherosclerosis (AS) is the formation of plaques in blood vessels, which leads to serious cardiovascular diseases. Current research has disclosed that the formation of AS plaques is highly related to the foaming of macrophages. However, there is a lack of detailed molecular biological mechanisms. We proposed a "live sensor" by grafting a tetrazine-based ratiometric NO probe within macrophages through metabolic and bio-orthogonal labeling. This "live sensor" was proved to target the AS plaques with a diameter of only tens of micrometers specifically and visualized endogenous NO at two lesion stages in the AS mouse model. The ratiometric signals from the probe confirmed the participation of NO during AS and indicated that the generation of endogenous NO increased significantly as the lesion progressed. Our proposal of this "live sensor" provided a native and smart strategy to target and deliver small molecular probes to the AS plaques at the in vivo level, which can be used as universal platforms for the detection of reactive molecules or microenvironmental factors in AS.


Radiologic-Pathologic Correlation of Primary and Secondary Cardiomyopathies: MR Imaging and Histopathologic Findings in Hearts from Autopsy and Transplantation.
Cardiac magnetic resonance (MR) imaging with late gadolinium enhancement (LGE) is used to detect and assess the myocardial damage seen with a variety of cardiomyopathies. Gadolinium-based contrast material accumulates in the expanded interstitial space of the myocardium. Areas with LGE correspond to replacement fibrosis, fibrofatty change, epithelioid granuloma, inflammatory cell infiltration, cardiomyocyte necrosis, and amyloid deposition-conditions that represent a focal increase in interstitial space. Areas without LGE correspond to interstitial or plexiform fibrosis, mildly degenerated cardiomyocytes, inflammatory cell infiltration, and diffuse amyloid deposition-conditions that represent diffuse increases in interstitial space. LGE MR imaging cannot depict these diffuse changes and does not enable quantitative evaluation of this increased interstitial space because on inversion-recovery MR images, the inversion time is adjusted to null the signal from normal-appearing or the least enhancing regions of the myocardium. Thus, the absence of LGE does not always indicate normal myocardial tissue. The use of current T1 mapping techniques enables one to overcome these drawbacks of LGE imaging, detect diffuse myocardial abnormalities, and perform quantitative analysis of the interstitial space. The authors describe the histopathologic and corresponding cardiac MR imaging findings of hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, cardiac sarcoidosis, giant cell myocarditis, and cardiac amyloidosis-mainly those seen on LGE MR images-as assessed by using whole-heart specimens obtained from autopsy or transplantation. ©RSNA, 2017.


Diagnosis and treatment of conjunctivitis in house finches associated with mycoplasmosis in Minnesota.
An ongoing outbreak of Mycoplasma gallisepticum-associated conjunctivitis in house finches (Carpodacus mexicanus) that began in 1994 in the eastern United States has been spreading westward. House finches presenting with the clinical signs of M. gallisepticum-associated conjunctivitis were first seen at the Wildlife Rehabilitation Center of Minnesota (Minnesota, USA) in July of 1996, and 42 cases were admitted from 26 December 1996 to 10 August 1997. A nested PCR was designed for sensitive and specific detection of the presence of the organism. Twelve birds were treated with oral enrofloxacin (15 mg/kg, twice daily for 21 days) and ophthalmic gentamicin (twice daily for 21 days). All treated birds showed resolution of clinical signs. Following treatment, finches were held for up to 6 mo and tested for the presence of M. gallisepticum by culture and nested polymerase chain reaction (PCR). Eight of twelve finches (67%) were positive for M. gallisepticum by nested-PCR and four (33%) were positive by culture. The results suggest that oral enrofloxacin and opthalmic gentamicin are not an effective treatment for the eradication of M. gallisepticum in house finches. Further, the results show that nested PCR is an effective method for detection of M. gallisepticum in house finches and was more sensitive than culture.


Frequency and severity of visual sensory and motor deficits in children with cerebral palsy: gross motor function classification scale.
Cerebral palsy (CP) is a permanent, nonprogressive disorder of movement and posture due to a lesion of the fetal or infant brain. The goal was to determine whether children with different severities of CP, as defined using the Gross Motor Function Classification System (GMFCS), had different degrees or types of visual dysfunction. An observational, cross-sectional-design study was conducted by using neurologic and masked ophthalmic measurements on a representative cohort of 50 children with CP. Mean age was 5.6 years (range, 2-19.5 years); mean gestational age was 31 weeks. The likelihood of debilitating visual deficits was greater in children with higher GMFCS scores, independent of gestational age. Children with level 5 disease (most severe) were at greatest risk for high myopia, absence of binocular fusion, dyskinetic strabismus, severe gaze dysfunction, and optic neuropathy or cerebral visual impairment (CVI). These deficits were rare or absent in children with the mildest disease, level 1. When categorized by anatomic or physiologic CP subtype, diplegic and spastic children were more often hyperopic and esotropic, but had the highest prevalence of fusion and stereopsis. In contrast, children with quadriplegic and mixed CP (dyskinetic, athetoid, hypotonic, and ataxic) more often had high myopia, CVI, dyskinetic strabismus, and gaze dysfunction. Visual deficits differ in children who have mild versus severe CP. Children with GMFCS level 1 to 2 have sensorimotor deficits resembling those of neurologically normal children with strabismus and amblyopia; children at level 3 to 5 have more severe deficits, not observed in neurologically normal children.


Trueness and Precision Achieved With Conventional and Digital Implant Impressions: A Comparative Investigation of Stone Versus 3-D Printed Master Casts.
To analyze implant casts obtained from intraoral optical scanning and conventional impressions. Ten optical scans (test) and ten conventional polyether impressions (control) were obtained from a two-implant reference model. Ten casts each were manufactured additively or from stone. All casts were digitized and virtually superimposed to the digital reference (trueness) applying a best-fit algorithm, and secondary analysis for intra-group comparisons (precision). The signed nearest neighbor distance of each surface point (FDI:24/26) was computed and deviations of the three-dimensional vectors (X,Y,Z) analyzed. The groups were compared with the Wilcoxon's rank sum test. The printed casts had mean deviations of 106.0μm and the stone casts 187.9μm compared to the reference. Controls had significantly higher deviations and dispersion (p⟨0.001). The printed casts showed mean intra-group deviations of 149.8μm and the stone casts 181.2μm without significant differences (p=0.162). There was no statistically significant difference in any of the vector analyses (X:p=0.105, Y:p=0.089, Z:p=0.123). Optical scanning seems to be an alternative to conventional impressions in terms of trueness and precision of implant master casts, simulating the scenario of a three-unit implant-supported fixed dental prosthesis. Digitally manufactured master casts might serve as reliable reference for the final restorations.


Transformation of cell type in uveal melanomas: a quantitative histologic analysis.
To describe the cytologic transformation and tumor progression in a series of uveal melanomas. Fifteen cases of uveal melanoma, treated by primary transscleral local resection without primary adjuvant treatment, needed enucleation because of local tumor recurrence. Cytologic and cell morphometric features of the primary tumor and the intraocular recurrence were compared, with evaluation of the amounts of intermediate cells, epithelioid cells, mitotic figures, and nucleolar area. The cases were categorized into 2 groups, according to their cytologic characteristics. In the first group (5 cases), there was no cytopathological transformation in the recurrent tumor. The nucleolar area was increased in only 1 case. In the second group (10 cases), the recurrent tumors showed transformation into a more epithelioid cell type. In all but 1 case there was an increase in epithelioid cells in the tumor recurrence. The nucleolar area was increased significantly in all cases. The mean local recurrence interval in all cases was 15.3 months, with no difference between the groups. Death from metastases occurred in 7 cases in which the nucleolar area was 4.2 microm(2) in the primary tumor. These findings demonstrate that, in an individual tumor, the cytologic phenotype can change considerably even after a relatively short time, resulting in an increase in tumor-related mortality. Studies on the natural course of uveal melanoma have been very limited and based purely on observations on the progression of melanomas in terms of size and alteration of various clinical characteristics.


Markerless registration for intracerebral hemorrhage surgical system using weighted Iterative Closest Point (ICP).
It is required to use a stereotactic frame on a patient's crainial surface to access an intracerebral hematoma in conventional ICH (Intracerebral Hemorrhage) removal surgery. Since ICH using a stereotactic frame is an invasive procedure and also takes a long time, we attempt to develop a robotic ICH removal procedure with a markerless registration system using an optical 3-D scanner. Preoperative planning is performed using a patient's CT (Computed Tomography) images, which include the patient's 3-D geometrical information on the hematoma and internal structures of brain. To register the preplanned data and the intraoperative patient's data, the patient's facial surface is scanned by an optical 3-D scanner on the bed in the operating room. The intraoperatively scanned facial surface is registered to the pose of the patient's preoperative facial surface. The conventional ICP (Iterative Closest Point) algorithm can be used for the registration. In this paper, we propose a weighted ICP in order to improve the accuracy of the registration results. We investigated facial regions that can be used as anatomical landmarks. The facial regions for the landmarks in the preoperative 3-D model are weighted for more accurate registration. We increase weights at the relatively undeformed facial regions, and decrease weights at the other regions. As a result, more accurate and robust registration can be achieved from the preoperative data even with local facial shape changes.


Factors modulating the activity of ornithine decarboxylase in rat HTC cells.
Dibutyryl cyclic AMP (dibu-cAMP), N1-acetylputrescine and both N1-acetylspermidine and N8-acetylspermidine regularly induce ornithine decarboxylase activity in both a time- and a concentration-dependent manner when added to HTC cells in suspension culture. N,N'-Diacetyl-1,6-diaminohexane and N-acetyl-1,3-diaminopropane, aliphatic analogues of acetylated putrescine containing the carboxamide bond but not known to occur naturally in animal tissues, are also effective inducing agents. The addition of 10(-2)M putrescine to the cell culture at the time of maximal induction of ODC in HTC cells by dibu-cAMP causes a marked decrease in the apparent half-life of ODC in less than 10 minutes. Ten-fold concentration of HTC cells at the time of their maximal induction by dibu-cAMP also results in an immediate decrease both in the specific activity of ODC and in its apparent half-life. When the population density of induced HTC cells is increased the relative effect of exposure of cells to increasing levels of putrescine is lessened. Some of the implications of these observations are discussed.


Age and breed differences in thyroid hormones, insulin-like growth factor (IGF)-I and IGF binding proteins in female horses.
A survey with horses was conducted to determine whether plasma concentrations of triiodothyronine (T3), thyroxine (T4), insulin-like growth factor (IGF)-I and IGF binding proteins (IGFBP) change as horses grow, mature sexually, and age. Jugular blood was sampled from Standardbred fillies and mares at ages 0, 1, 7, and 14 d, at 1, 2, 4, 5, 6, and 9 mo, and at 5 to 8 and 16 to 22 yr (n = 5 to 18). In a second survey, we measured the same variables in eight breeds of horses with markedly different adult body sizes, from Miniatures to Friesians. Plasma T3, T4, and IGF-I were determined by radioimmunoassays validated for horses, and IGFBP were estimated from radioligand assay following separation of the IGFBP by SDS-PAGE electrophoresis. Plasma T3 decreased (P < .01) nearly continuously from 7.9 ng/mL on the day of birth to .9 ng/mL at 6 mo, and then changed little from .7 ng/mL at 9 mo to .5 ng/mL in mares 16 to 22 yr old. Similarly, T4 declined (P < .01) from 233 ng/mL on the day of birth to 49 ng/mL at 14 d and varied from 35 to 9 ng/mL among all of the older age groups. Plasma concentrations of IGF-I increased (P < .01) from 285 ng/mL on the day of birth to 572 ng/mL at 14 d, remained relatively constant until 9 mo of age (530 ng/mL), and then declined (P < .01) to low levels (295 ng/mL) in the oldest mares. We detected six IGFBP. The two smallest IGFBP (26 and 39 kDa) were highest during the first 14 d after birth and lowest (P < .01) in aged mares. The four larger IGFBP were lowest at birth and increased to the highest values during the most rapid growth period, but these changes were not significant (P > .20). In agreement with data for other species, our data suggest that IGF-I and IGFBP modulate growth in horses. Although there were impressive interbreed differences in circulating concentrations of T3, T4, IGF-I, and IGFBP, these were not related to differences in adult body size.


Total knee replacement with a variable axis knee prosthesis.
The Variable Axis Knee Prosthesis was designed to accommodate a wide range of problems in the knee and to minimize the complication of loosening. The results of the series, which now spans over seven years at this institution, have confirmed the effectiveness of the prosthesis in providing stability and firm fixation. Patellar alignment remains critical for optimum results. A wide variety of abnormalities, including failed prostheses, severe flexion contractures, arthrodesed knees, and severely osteoporotic bone, can be effectively managed utilizing this device. As with any other total knee prosthesis, the use of this prosthesis should be restricted to those knees with definite radiographic evidence of joint impairment in addition to significant symptoms. Relative contraindications include previous sepsis, neuropathic joint disease, and gross ligamentous incompetency. If these indications and limitations are adhered to, the results from knee replacement can be expected to equal or exceed those from total hip replacement over the long term.


Aggregation induced emission-based fluorescent nanoparticles: fabrication methodologies and biomedical applications.
Novel fluorescent nanoparticle (FNP)-based bioprobes are expected to generate new medical diagnostic techniques in biomedical and biological areas for their superior brightness and photostability compared with conventional molecular probes including small organic dyes and fluorescent proteins. Potentially interesting nanoscale platforms for various biomedical applications are greatly attractive due to the potential to avoid exposure of human tissues to toxic drugs, enhancing delivery of hydrophobic therapeutics and fabricating multifunctional imaging, targeting and delivery system. In this review, recent progress in the area of novel aggregation induced emission (AIE)-based FNPs is summarized over the past few years (2007-2013), and the reported fabrication methodologies of these fluorescent systems including non-covalent and covalent strategies are mainly discussed, and the biomedical applications of AIE-based FNPs are also summarized.


Brain Imaging: A Decade of Coverage in the Print Media.
Advances in neuroscience are increasingly intersecting with issues of ethical, legal, and social interest. This study is an analysis of press coverage of an advanced technology for brain imaging, functional magnetic resonance imaging, that has gained significant public visibility over the past ten years. Discussion of issues of scientific validity and interpretation dominated over ethical content in both the popular and specialized press. Coverage of research on higher order cognitive phenomena specifically attributed broad personal and societal meaning to neuroimages. The authors conclude that neuroscience provides an ideal model for exploring science communication and ethics in a multicultural context.